The present invention relates generally to monitoring phase transitions in materials and, more particularly, to a method for monitoring the crystallization of an organic material from a liquid using second harmonic generation.
By providing the appropriate thermal or mechanical input, phase transitions may be induced in materials. Phase transitions are generally identified by monitoring changes in a physical property or properties of the material during thermal and/or mechanical input. The elucidation of the phase transition behavior of a material is important in understanding the properties of the material. Thus, the development of methods for identifying and probing phase transitions in materials is of great interest.
Many materials, such as organic and inorganic compounds and polymers, exhibit polymorphism, i.e. they can exist in more than one crystallographically distinct crystalline phase. These crystalline phases, known as polymorphs, may be centrosymmetric phases that have inversion symmetry, or non-centrosymmetric crystalline phases that do not have inversion symmetry.
Although the individual polymorphs of a polymorphic material have the same chemical composition, they can have significantly different physical properties. This may be illustrated using, for example, the energetic, polymorphic organic compound octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX). Four distinct, crystalline phases (i.e. 4 polymorphs) have been identified for HMX. Two of these polymorphs, xcex2-HMX and xcex4-HMX, differ in their sensitivity to temperature and pressure. The beta phase of HMX (xcex2-HMX) is relatively insensitive to changes in temperature and pressure. However, explosive decomposition may be induced more readily in the delta phase of HMX (xcex4-HMX) with thermal and/or shock input.
Many important biologically active pharmaceutical compounds are polymorphic. The phase behavior and physical properties of polymorphic pharmaceutical compounds must be thoroughly understood, since the properties of the various polymorphs of a polymorphic pharmaceutical compound may be different. For example, individual polymorphs of a polymorphic pharmaceutical compound can exhibit different rates of dissolution, which can affect their concentration in body tissues and therefore their effectiveness. Examples of polymorphic pharmaceuticals include the anti-diabetic drug tolbutamide, the antibiotic chloramphenicol, and the selective estrogen response modulator tamoxifen. For a review of polymorphic pharmaceutical compounds, see L. Borka and J. K. Haleblian, Acta. Pharm. Jugosl. 40, 1 (1990) hereby incorporated by reference.
The development of crystallization procedures to induce the formation of a desired polymorph is usually expensive and time consuming. Optimizing these procedures usually involves determining operating temperatures, operating pressures, rates of heating or cooling, solvents, concentrations of materials, and other parameters. Rapid non-invasive, in-situ, dynamic monitoring during crystallization can provide important information regarding the formation of desired and undesired polymorphs of polymorphic materials. While calorimetry, Infrared and Raman spectroscopy, and x-ray diffraction have traditionally been used for the detection of polymorphic transitions, system costs are prohibitively expensive at the laboratory scale, and will likely limit their use in situ on the industrial scale.
It is extremely important to understand the phase behavior of polymorphic materials. Clearly, a rapid and sensitive method for identifying and probing the phase transitions of polymorphic materials is highly desirable.
Therefore, an object of the present invention is to provide a rapid and highly sensitive method for identifying and probing phase transitions of polymorphic materials.
Another object of the present invention is to provide a method for monitoring the crystallization of an organic material from a liquid.
Yet another object of the present invention is to provide a method for detecting the crystallization of centrosymmetric and non-centrosymmetric polymorphs.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.
To achieve the foregoing and other objects, and in accordance with the purposes of the present invention as embodied and broadly described herein, the invention includes a method for monitoring the crystallization of at least one organic material from a liquid. According to the method, a liquid having at least one organic material capable of existing in at least one non-centrosymmetric phase is prepared. The liquid is interrogated with a laser beam at a chosen wavelength. As at least a portion of the at least one organic material crystallizes from the liquid, the intensity of any light scattered by the crystallized material at a wavelength equal to one-half the chosen wavelength of the interrogating laser beam is monitored.
The invention also includes method of monitoring the crystallization of at least one organic material from a liquid reaction mixture during a chemical reaction. According to the method, a liquid reaction mixture is subjected to conditions that promote a chemical reaction that produces at least one crystalline organic material having at least one non-centrosymmetric phase. As the at least one crystalline organic material is produced, the liquid reaction mixture is interrogated with a laser beam at a chosen wavelength. Meanwhile, the intensity of any light scattered by the crystallized organic material is monitored at a wavelength equal to one-half the chosen wavelength of the interrogating laser beam.